Coperin - · PDF fileCoperin Capsule is a delayed release capsule for oral ... Empty Hard...

Coperin Duloxetine (as hydrochloride)

PRODUCT INFORMATION

NAME OF THE MEDICINE

Active ingredient : Duloxetine (as hydrochloride)

Chemical name : (+)-(S)-N-methyl-γ-(1-naphthalenyloxy)-2-thiophenepropanamine hydrochloride

Structural formula :

Molecular formula : C18H19NOS.HCl Molecular weight : 333.9

CAS Registry no. : 136434-34-9

DESCRIPTION

Duloxetine Hydrochloride

Duloxetine Hydrochloride is a selective serotonin and noradrenaline reuptake inhibitor (SNRI) for oral

administration. It is chemically unrelated to tricyclics, alpha adrenergic receptor agonists or antimuscarinics. . It

is a white to cream coloured powder, which is sparingly soluble in water, freely soluble in methanol and

practically insoluble in hexane.

Coperin Capsule is a delayed release capsule for oral administration. Each capsule contains enteric-coated mini

tablets of duloxetine hydrochloride equivalent to 30 mg or 60 mg of duloxetine that are designed to prevent

degradation of the drug in the acidic environment of the stomach.

Excipients

Inactive ingredients include Lactose, Croscarmellose Sodium, Pregelatinised maize starch, Polysorbate 80,

Magnesium stearate, Hypromellose, Hypromellose phthalate, Purified talc, Triethyl citrate,

Empty Hard Gelatin Capsule:

The 30 mg capsule is a Size 3 hard gelatin capsule (ARTG No. 108081) with a dark blue cap and a white body

and contains Indigo carmine CI73015, Gelatin, Titanium dioxide and Sodium lauryl sulfate.

The 60 mg capsule is a Size 1 hard gelatin capsule (ARTG No. 108080) with a dark blue cap and a green body

and contains Indigo carmine CI73015, Gelatin, Titanium dioxide, Iron oxide yellow CI77492 and Sodium

lauryl sulfate.

Coperin – PRODUCT INFORMATION 2

Both capsule shells are imprinted with TekPrint SW-900B Black Ink, (ARTG No. 2328) and TekPrint SW-

0012 White Ink (ARTG No. 13175).

PHARMACOLOGY

Pharmacodynamic properties and Mechanism of Action

Duloxetine is a selective serotonin and noradrenaline reuptake inhibitor, and weakly inhibits dopamine uptake

with no significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors.

Although the mechanism of the antidepressant action of duloxetine in humans is unknown, it is believed to be

related to its potentiation of serotonergic and noradrenergic activity in the CNS. Duloxetine dose-dependently

increased extracellular levels of serotonin and noradrenaline in selected brain areas of animals, and

neurochemical and behavioural studies in animals indicate an enhancement of central serotonin and

noradrenaline neurotransmission. Duloxetine undergoes extensive metabolism, but the major circulating

metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.

Duloxetine displayed analgesic activity in rodent models of persistent, inflammatory or neuropathic pain, but

not acute or arthritic pain.

Pharmacokinetics

Absorption

In humans, orally administered duloxetine hydrochloride is well absorbed with maximal plasma concentrations

(Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine, however food can

delay the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of

absorption (AUC) by about 11%.

Duloxetine plasma exposure increases in proportion to dose for doses up to 60 mg twice a day. Steady-state

plasma concentrations are typically achieved after 3 days of dosing. Based upon AUC, multiple once daily

doses of 60 mg produce steady-state concentrations that are approximately 1.5 times higher than that predicted

from a 60 mg single dose. Average minimum and maximum steady-state concentrations for the 60 mg once

daily dose are 27.0 and 89.5 ng/mL, respectively. There is no clinically important difference in the

pharmacokinetic parameters of morning and evening doses.

Distribution

Following oral administration, the apparent volume of distribution of duloxetine averages 1640 L. Duloxetine is

highly protein bound (>90%) to plasma proteins but protein binding is not affected by renal or hepatic

impairment. Duloxetine binds to both albumin and α1-acid glycoprotein.

Metabolism

Duloxetine undergoes extensive metabolism. The 2 major metabolites found in plasma and urine are the

glucuronide conjugate of 4-hydroxy duloxetine, and the sulfate conjugate of 5-hydroxy, 6-methoxy duloxetine.

Both CYP2D6 and CYP1A2 catalyse the formation of the initial oxidation steps to form

4-, 5-, and 6-hydroxy duloxetine. The metabolites circulating in plasma are in the conjugated form and are not

pharmacologically active.

Excretion

The half-life of duloxetine (unchanged drug) is 12.1 hours. Apparent plasma clearance of duloxetine after an

oral dose is 101 L/hr. The majority (70%) of the duloxetine dose is recovered in the urine as conjugated

metabolites of oxidative metabolites of duloxetine. Approximately 20% of the dose is recovered in the faeces as

unchanged drug, unconjugated metabolites, or unidentified compounds. Only trace (<1% of the dose) amounts

of unchanged duloxetine are present in the urine.


Special Populations

Gender

Apparent plasma clearance was lower in females; however this difference in clearance values does not appear

to be clinically significant. The mean half-life of duloxetine was similar between males and females. Dosage

adjustment based on gender is not necessary.

Elderly

Population pharmacokinetic analyses suggest no significant effect of age on the pharmacokinetics of duloxetine

in adult male and female patients with major depressive disorder. Dosage adjustment based on age is not

necessary for elderly patients.

Children and Adolescents <18 years old

The pharmacokinetics of duloxetine have not been studied in children and adolescents <18 years old.

Race

No specific pharmacokinetic study was conducted to investigate the effects of race. Due to large interpatient

variability, clinically significant differences in drug level exposure among ethnic groups are not likely.

Smoking Status

Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications

are not recommended for smokers.

Renal Impairment

Duloxetine Cmax and AUC values were approximately 2-fold higher in patients with end stage renal disease

(ESRD) receiving chronic intermittent dialysis, compared with subjects with normal renal function. In contrast,

the elimination half-life was similar in both groups. A lower dose should be used for patients with ESRD (see

DOSAGE AND ADMINISTRATION). Population pharmacokinetic analyses suggest that mild renal

dysfunction has no significant effect on apparent plasma clearance of duloxetine.

Hepatic Impairment

Mean duloxetine apparent plasma clearance of patients with moderate cirrhosis of the liver was approximately

15% of that of healthy subjects. The Cmax was similar but the half-life was 34 hours longer. Duloxetine is

contraindicated in patients with hepatic impairment (see CONTRAINDICATIONS).

CLINICAL TRIALS

Acute treatment of depression:

The efficacy of duloxetine has been evaluated in six double-blind, placebo-controlled acute Phase 3 studies of

8-9 weeks' duration in 1978 adult outpatients (18 to 83 years) meeting the DSM-IV criteria for major

depression at doses of 40 mg to 120 mg daily. In four of these studies, duloxetine was significantly superior to

placebo as measured by the mean change in the 17 item Hamilton Depression Rating Scale (HAMD17) total

score from baseline to endpoint. Duloxetine doses in these four studies were:

60 mg once daily (two studies)

20 mg twice daily and 40 mg twice daily (one study)

40 mg twice daily and 60 mg twice daily (one study)


In the remaining two studies duloxetine showed numerically superior mean change compared with placebo. The

duloxetine doses in these two studies were:

20 mg twice daily and 40 mg twice daily

40 mg twice daily and 60 mg twice daily

In both of these latter studies, the active comparator paroxetine also did not separate significantly from placebo

on the primary outcome measure. Response (> 50% reduction in HAMD17 total score) and remission (HAMD17

total score < 7) were also significantly higher with duloxetine compared with placebo in five out of six and

three out of six acute studies, respectively.

While results were positive for improvement in the HAMD17 at a dose of 20 mg twice daily in one of two

studies, this dose did not demonstrate statistical superiority on any other measure including response or

remission

Table 1 HAMD17 Total, Response, and Remission Rates Placebo-Controlled Duloxetine 60mg Once Daily

Studies

1 Least-squares mean change from baseline

2 Response = ≥50% reduction in HAMD17 total score from baseline to endpoint

3 Remission = HAMD17 total score ≤ 7 at endpoint

4 P-values for the HAMD17 Total are from analysis of covariance and for response and remissions are from

Fisher’s exact test

In addition to the HAMD17 total score, several other measures were included in the evaluation of efficacy of

duloxetine. HAMD17 Depressed Mood Item (Item 1), the Anxiety Subfactor of the HAMD17, the Patient Global

Impressions (PGI) Improvement Score, bodily pain as measured by Visual Analog Scale (VAS), and the

Quality of Life in Depression rating scales were also examined. In the four studies where duloxetine

demonstrated statistical superiority over placebo as measured by improvement in the HAMD17 total score,

results were also positive for the additional measures at doses of 60 mg to 120 mg per day.

In each study and in pooled data, the effectiveness of duloxetine was similar regardless of age, gender or racial

origin.

Prevention of depressive relapse

Patients responding to 12 weeks of acute treatment with open-label duloxetine at a dose of 60 mg once daily

were randomly assigned to either duloxetine 60 mg once daily or placebo for a further 6 months (continuation

phase) and time to relapse in each group was compared. Of 533 subjects who enrolled in the study, 278

responded and were randomised to duloxetine 60 mg once daily (n=136) or placebo (n=142). The estimated

probability of depressive relapse at 6 months for placebo was 38.3% and for duloxetine 60 mg once daily was

19.7% (p=0.004). During the 6-month continuation therapy phase of this study, 17.4% of duloxetine-treated

patients met the a priori-defined criteria for relapse compared with 28.5% on placebo (p=0.042).

Of 88 patients who relapsed during the continuation phase, 87 received double-blind rescue therapy. The

patients who relapsed on placebo (n=58) were treated with duloxetine at a dose of 60 mg once daily, and those

relapsing on duloxetine 60 mg once daily (n=29) were treated with duloxetine 60 mg twice daily. Of those

patients relapsing on placebo and treated with duloxetine 60 mg once daily, response (50% reduction in

HAMD17 total score) occurred in 77% and remission (HAMD17 total score < 7) occurred in 57% at the end of

12 further weeks of treatment. Of those patients who relapsed on duloxetine 60 mg once daily and who were

treated with an increased dose of 60 mg twice daily, 62% met response criteria and 38% met remission criteria.

HMBHa HMBHb

Placebo

(n=115)

Duloxetine

(n=121)

P-

Value4

Placebo

(n=136)

Duloxetine

(n=123)

P-

Value4

HAMD17

Total1

-5.67 -9.47 <0.001 -7.02 -8.75 0.048

Response2

27 (23%) 55 (45%) <0.001 48 (35%) 62 (50%) 0.017

Remission3

17 (15%) 38 (31%) 0.003 33 (24%) 39 (32%) 0.212


Use in elderly patients with depression

The efficacy and safety of duloxetine 60 mg once daily (n=207) and placebo (n=104) have been compared in

the acute treatment (study duration 8 weeks) of elderly patients with MDD (>65 years of age, mean age 72.9

years). Duloxetine treated patients experienced improvement in depressive symptoms, as assessed by the

Geriatric Depression Scale, from week 1, with least-squares mean changes from baseline to endpoint of -1.34

for placebo-treated patients and -4.07 for duloxetine-treated patients (p<0.001). On the Hamilton Depression

Rating Scale, least squares mean changes from baseline to endpoint for total HAMD score were -3.72 for

placebo-treated patients and -6.49 for duloxetine-treated patients (p<0.001). Duloxetine-treated patients also

experienced a greater improvement in composite cognitive score than the placebo-treated patients. The least-

squares mean change from baseline to endpoint for the composite cognitive score was 0.76 in placebo-treated

patients and 1.95 for duloxetine-treated patients (p=0.013).

General Anxiety Disorder

The efficacy of duloxetine has been established in 5 Phase 3 clinical trials. Four of the studies were acute

placebo-controlled studies and the fifth was a relapse prevention study. Of the four placebo controlled studies

one was a fixed dose study while the other three were flexible dose studies.

Study HMBR (fixed dose) was a randomised double blind trial designed to assess whether duloxetine 120mg

once daily (QD) was superior to placebo in the treatment of GAD as measured by the mean change in Hamilton

Anxiety Depression Rating Scale (HAMA) during the 9-week, double-blind, acute therapy phase. A key

secondary objective was to assess whether duloxetine 60mg QD was superior to placebo in the treatment of

GAD during the 9-week, double blind acute therapy phase.

Studies HMDT, HMDU and HMDW, respectively, were Phase 3 (flexible dose) randomised double-blind

placebo-controlled studies that used the same primary objective: to assess whether duloxetine flexibly dosed

from 60 mg to 120 mg QD was superior to placebo in the treatment of GAD as measured by mean change in

HAMA total score over 10 weeks. Venlafaxine 75 mg to 225 mg QD was used as an active comparator in

studies HMDU and HMDW and data from these trials was combined (designed a priori) to have sufficient

power for non-inferiority comparison of duloxetine with venlafaxine. For all 3 studies doses were increased at

specified visits if the CGI-Improvement score remained at 3 or below or minimally improved.

In all 4 acute placebo controlled studies the mean decrease in HAMA total score was significantly greater for

duloxetine-treated patients compared with placebo treated patients as shown in Table 2

Table 2 Summary of Primary Efficacy in acute placebo-controlled GAD studies

Study/

duration

Treatment Group N Baseline Endpoint LSMean

Change

p-value

vs placebo

HMBR

9 weeks

Duloxetine 60 mg QD Duloxetine

120 mg QD

Placebo

165

169

173

25.05

25.13

25.82

12.32

12.74

17.19

-12.8

-12.5

-8.4

<.001

<.001

-

HMDT

10 weeks

Duloxetine 60 to 120 mg QD

Placebo

161

158

22.54

23.49

14.27

17.00

-8.1

-5.9

.023

-

HMDU

10 weeks

Duloxetine 60 to 120 mg QD

Venlafaxine 75 to 225 mg QD

Placebo

149

159

158

25.77

24.92

24.98

13.95

12.90

16.06

-11.8

-12.4

-9.2

.007

<.001

-

HMDW

10 weeks

Duloxetine 20 mg QD Duloxetine

60 to 120 mg QD Venlafaxine 75

to 225 mg QD

Placebo

83

151

158

163

27.65

27.74

27.36

27.33

12.49

11.85

11.66

15.77

-14.7

-15.3

-15.5

-11.6

.007

<.001

<.001

-

QD = once daily.

Duloxetine at the recommended dose of 60 mg to 120 mg once daily demonstrated statistically significant

superiority over placebo as measured by improvement in the Hamilton Anxiety Scale (HAM-A) total score and

by the Sheehan Disability Scale (SDS) global functional impairment score.

Response and remission rates were also higher with Duloxetine compared to placebo. Duloxetine showed

comparable efficacy results to venlafaxine in terms of improvements on the HAM-A total score.


In study HMDV, a relapse prevention study, patients responding to 6 months of acute treatment with open-label

duloxetine were randomised to either duloxetine or placebo for further 6-months. Duloxetine 60 mg to 120 mg

once daily demonstrated statistically significant superiority compared to placebo (p<0.001) on the prevention of

relapse, as measured by time to relapse. The incidence of relapse during the 6-months double-blind follow-up

period was 14% for Duloxetine and 42% for placebo.

INDICATIONS

Duloxetine is indicated for the treatment of major depressive disorder (MDD).

Duloxetine is indicated for the treatment of generalised anxiety disorder (GAD).

CONTRAINDICATIONS

Duloxetine is contraindicated in patients with known hypersensitivity to duloxetine or to any of the excipients

in the formulation.

The concomitant use of monoamine oxidase inhibitors (MAOIs) with duloxetine is contraindicated. Duloxetine

should not be administered within at least 14 days of discontinuing treatment with an MAOI. At least 5 days

should elapse after stopping duloxetine, before starting an MAOI.

Duloxetine is contraindicated in patients with liver disease resulting in hepatic impairment (see

PHARMACOLOGY - Pharmacokinetics).

Duloxetine should not be used in combination with potent CYP1A2 inhibitors (see INTERACTIONS WITH

OTHER MEDICINES).

PRECAUTIONS

Clinical Worsening and Suicide Risk

The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. This risk

must be considered in all depressed patients.

Patients with depression may experience worsening of their depressive symptoms and/or the emergence of

suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and

this risk may persist until significant remission occurs. As improvement may not occur during the first few

weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality,

especially at the beginning of a course of treatment, or at the time of dose changes, either increases or

decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing

the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe,

abrupt in onset, or was not part of the patient's presenting symptoms. Patients (and caregivers of patients)

should be alerted about the need to monitor for any worsening of their condition and/or the emergence of

suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these

symptoms present. Patients with co-morbid depression associated with other psychiatric disorders being treated

with antidepressants should be similarly observed for clinical worsening and suicidality.

Pooled analyses of 24 short-term (4 to 16 weeks), placebo-controlled trials of nine antidepressant medicines

(SSRIs and others) in 4400 children and adolescents with major depressive disorder (16 trials), obsessive

compulsive disorder (4 trials) or other psychiatric disorders (4 trials) have revealed a greater risk of adverse

events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those

receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4%

compared with 2% of patients given placebo. There was considerable variation in risk among the

antidepressants, but there was a tendency towards and increase for almost all antidepressants studied. The risk

of suicidality was most consistently observed in the major depressive disorder trials, but there were signals of

risk arising from trials in other psychiatric indications (obsessive compulsive disorder and social anxiety

disorder) as well. No suicides occurred in these trials. It is unknown whether the suicidality risk in children and


adolescent patients extends to use beyond several months. The nine antidepressant medications in the pooled

analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs

(bupropion, mirtazapine, nefazodone, venlafaxine).

Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity,

akathisia (psychomotor restlessness), hypomania and mania have been reported in adults, adolescents and

children being treated with antidepressants for major depressive disorder as well as for other indications, both

psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either

worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that

such symptoms may be precursors of emerging suicidality.

Families and caregivers of children and adolescents being treated with antidepressants for major depressive

disorder or for any other condition (psychiatric or nonpsychiatric) should be informed about the need to monitor

these patients for the emergence of agitation, irritability, unusual changes in behaviour and other symptoms

described above, as well as the emergence of suicidality, and to report such symptoms immediately to

healthcare providers. It is particularly important that monitoring be undertaken during the initial few months of

antidepressant treatment or at times of dose increase or decrease.

Duloxetine has not been studied in patients under the age of 18 and is not intended for use in this age group.

Although a causal role for duloxetine in inducing such events has not been established, some analyses from

pooled studies of antidepressants in psychiatric disorders found an increased risk for suicidal ideation and/or

suicidal behaviors in pediatric and young adult (<25 years of age) patients compared to placebo (see

PRECAUTIONS - Depression).

Physicians should encourage patients to report any distressing thoughts or feelings at any time.

Prescriptions for duloxetine should be written for the smallest quantity of capsules consistent with good patient

management, in order to reduce the risk of overdose.

Hepatotoxicity

Duloxetine should ordinarily not be prescribed to patients with evidence of acute or chronic liver disease as it is

possible that duloxetine may aggravate pre existing liver disease (see CONTRAINDICATIONS).

Duloxetine increases the risk of elevation of serum transaminase levels. Liver transaminase elevations resulted

in the discontinuation of 0.3% (82/27,229) of duloxetine treated patients. In these patients, the median time to

detection of the transaminase elevation was about two months. In placebo controlled trials in any indication,

elevations of alanine transaminase (ALT) to >3 times the upper limit of normal occurred in 1.1% (85/7632) of

duloxetine treated patients and in 0.2% (13/5578) of placebo treated patients. In placebo-controlled studies

using a fixed dose design, there was evidence of a dose-response relationship for ALT and AST elevation of >3

times the upper limit of normal and >5 times the upper limit of normal, respectively.

Postmarketing reports have described cases of hepatitis with abdominal pain, hepatomegaly and elevation of

transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a

mixed or hepatocellular pattern of liver injury. Cases of cholestatic jaundice with minimal elevation of

transaminase levels have also been reported. Isolated cases of liver failure, including fatal cases, have been

reported. A majority of these cases have been reported in patients with past or current risk factors for liver

injury, including alcohol abuse, hepatitis or exposure to drugs with known adverse effects on the liver.

The combination of transaminase elevations and elevated bilirubin, without evidence of obstruction, is

generally recognised as an important predictor of severe liver injury. In clinical trials, 7 duloxetine patients had

elevations of transaminases and bilirubin, but 5 of 7 also had elevation of alkaline phosphatase, suggesting an

obstructive process; in these patients, in 3 of these 7 patients there was evidence of heavy alcohol use and this

may have contributed to the abnormalities seen.

Postmarketing reports indicate that elevated transaminases, bilirubin and alkaline phosphatase have occurred in

patients with chronic liver disease or cirrhosis.


Alcohol

Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may

aggravate pre-existing liver disease, duloxetine should ordinarily not be prescribed to patients with substantial

alcohol use or evidence of chronic liver disease (see PRECAUTIONS - Hepatotoxicity)

Activation of Mania

In placebo-controlled trials in patients with major depressive disorder, activation of hypomania or mania

occurred in 0.1% of duloxetine treated patients and 0.1% of placebo treated patients. No activation of mania or

hypomania was reported in DPNP or GAD placebo controlled trials. Activation of mania/hypomania has been

reported in a small proportion of patients with mood disorders who were treated with other marketed drugs

effective in the treatment of major depressive disorder. As with these other drugs, duloxetine should be used

cautiously in patients with a history of mania.

Seizures

Duloxetine has not been systematically evaluated in patients with a seizure disorder. In placebo-controlled

clinical trials, seizures/convulsions occurred in 0.03% (3/9445) of patients treated with duloxetine and 0.01%

(1/6770) of patients with placebo. As with similar CNS active drugs, duloxetine should be used cautiously in

patients with a history of seizure disorder.

Mydriasis

Mydriasis has been reported in association with duloxetine. Caution should be exercised in patients with raised

intraocular pressure or those at risk of acute narrow-angle glaucoma.

Hyponatraemia

Hyponatraemia has been reported very rarely, predominantly in the elderly, when administering duloxetine.

Caution is required in patients at increased risk for hyponatraemia; such as elderly, cirrhotic, or dehydrated

patients or patients treated with diuretics. Hyponatraemia may be due to a syndrome of inappropriate anti-

diuretic hormone secretion (SIADH).

Abnormal Bleeding

SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events, including gastrointestinal

bleeding (see ADVERSE EFFECTS). Therefore, caution is advised in patients taking duloxetine

concomitantly with anticoagulants and/or medicinal products known to affect platelet function (e.g., NSAIDs,

aspirin) and in patients with known bleeding tendencies.

Use in Patients with Concomitant Illness

Clinical experience with duloxetine in patients with concomitant systemic illnesses is limited. Caution is

advisable in using duloxetine in patients with diseases or conditions that produce altered metabolism or

haemodynamic responses.

Duloxetine has not been systematically evaluated in patients with a recent history of myocardial infarction or

unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the

product's premarketing testing. However, evaluation of electrocardiograms (ECGs) of 321 patients who

received duloxetine in placebo-controlled clinical trials indicated that duloxetine is not associated with the

development of clinically significant ECG abnormalities (see PRECAUTIONS - Electrocardiogram

Changes).

Increased plasma concentrations of duloxetine occur in patients with end stage renal disease (ESRD) and in

patients with moderate hepatic impairment (see PHARMACOLOGY – Pharmacokinetics).


Drug Dependence

While duloxetine has not been systematically studied in humans for its potential for abuse, there was no

indication of drug-seeking behaviour in the clinical trials. However, it is not possible to predict on the basis of

premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once

marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow

such patients closely, observing them for signs of misuse or abuse of duloxetine (e.g. development of tolerance,

incrementation of dose, drug-seeking behaviour).

Weight Changes

Weight changes do not appear to be clinically significant outcomes of treatment with duloxetine. In placebo-

controlled clinical trials, patients treated with duloxetine for up to 9-weeks experienced a mean weight loss of

approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients.

Renal Impairment

Duloxetine Cmax and AUC values were approximately 2-fold higher in patients with ESRD receiving chronic

intermittent dialysis, compared with subjects with normal renal function. In contrast, the elimination half-life

was similar in both groups. A lower dose should be used for patients with ESRD (see DOSAGE AND

ADMINISTRATION). Population pharmacokinetic analyses suggest that mild renal dysfunction has no

significant effect on apparent plasma clearance of duloxetine.

Blood Pressure

Duloxetine is associated with an increase in blood pressure in some patients. In placebo-controlled clinical trials

duloxetine treatment was associated with small increases in systolic blood pressure averaging 2 mm Hg and

small increases in diastolic blood pressure averaging 0.5 mm Hg compared to placebo. Large, potentially

clinically significant, elevations in blood pressure do not appear to be more common with duloxetine than with

placebo. In patients with known hypertension and/or other cardiac disease, blood pressure monitoring is

recommended as appropriate. Duloxetine should be used with caution in patients whose conditions could be

compromised by an increased heart rate or by an increase in blood pressure.

Orthostatic Hypotension and Syncope

Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine. Syncope and

hypotension tend to occur within the first week of therapy but can occur at any time during duloxetine

treatment, particularly after dose increases. The risk of blood pressure decreases may be greater in patients

taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent

CYP1A2 inhibitors and in patients taking doses above 60 mg daily. Consideration should be given to

discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or syncope

during therapy.

Electrocardiogram Changes

ECGs were obtained from 321 duloxetine-treated patients with MDD and 169 placebo-treated patients in 8-

week clinical trials. The rate-corrected QT interval in duloxetine-treated patients in an 8-week study did not

differ from that seen in placebo-treated patients. In summary, the data suggest no arrhythmogenic potential with

duloxetine. No clinically significant differences were observed for QT, PR and QRS intervals between

duloxetine-treated and placebo-treated patients.

Discontinuing Treatment

As with other drugs effective in the treatment of major depressive disorder, when discontinuing Duloxetine

after more than 1 week of therapy, it is generally recommended that the dose be tapered to minimise the risk of

discontinuation symptoms (see DOSAGE AND ADMINISTRATION). The most commonly reported

symptoms following abrupt discontinuation of duloxetine in clinical trials have included dizziness, nausea,

headache, paraesthesia, fatigue, vomiting, irritability, nightmares, insomnia, diarrhoea, anxiety, hyperhidrosis

and vertigo.


Serotonin Syndrome

Serotonin syndrome, a potentially life threatening condition, has been reported in patients using SSRIs (e.g.

paroxetine, fluoxetine) concomitantly with serotonergic medicinal products including tramadol. As with other

serotonergic agents, serotonin syndrome has been reported with duloxetine treatment. Caution is advisable if

duloxetine is used concomitantly with serotonergic antidepressants like SSRIs, SNRIs, tricyclic antidepressants

like clomipramine or amitriptyline, St John's Wort (Hypericum perforatum), or triptans, tramadol, pethidine and

tryptophan.

Effects on Fertility

Duloxetine administered orally to male rats prior to and throughout mating, or to female rats prior to and

throughout mating, gestation and lactation, at doses up to 45 mg/kg (3 times the MRHD on a mg/m2 basis) did

not alter mating or fertility. In females, this dose was associated with oestrus cycle disruption and signs of

maternotoxicity and embryofoetal toxicity.

Use in Pregnancy - Category B3

Duloxetine and/or its metabolites cross the placenta in rats. There was no evidence of teratogenicity in rats or

rabbits following oral administration of duloxetine during the period of organogenesis at doses up to 45

mg/kg/day. In rats, this dose was 3 times the maximum recommended human dose on a mg/m2 basis. In rabbits,

the estimated systemic exposure (plasma AUC) at this dose was less than clinical exposure at the maximum

recommended dose. In rats receiving the maternotoxic dose of 45 mg/kg/day during organogenesis, there was

increased preimplantation loss and resorptions, and reduced foetal weight.

Oral administration of duloxetine to female rats prior to and throughout mating, gestation and lactation at doses

of 30-45 mg/kg/day (2-3 times the maximum recommended human dose on a mg/m2 basis) elicited maternal

toxicity and reduced live birth indices, birth weight, and postnatal survival and growth of offspring, and altered

some indices of offspring behaviour.

Neonates exposed to serotonergic agents late in the third trimester have been uncommonly reported to have

clinical findings of respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty,

vomiting, hypoglycaemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant

crying. Such events can arise immediately upon delivery and are usually transient. These features could be

consistent with either a direct effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. When

treating a pregnant woman with duloxetine during the third trimester, the physician should carefully consider

the potential risks and benefits of treatment.

The safety of duloxetine in human pregnancy has not been established and because animal reproduction studies

are not always predictive of human response, this drug should be used during pregnancy only if the potential

benefit justifies the potential risk.

Use in Lactation

Duloxetine is excreted into the milk of lactating women. The estimated infant dose ranges from approximately

0.1% to 0.3% of the maternal dose, normalised by body weight. Oral administration of duloxetine to female rats

prior to and throughout mating, gestation and lactation was associated with maternal toxicity and adverse

effects (see Use in Pregnancy). Administration of duloxetine to nursing mothers is not recommended.

Use in Patients aged >65 years of age

Evaluation of patients over the age of 65 who received duloxetine revealed no unusual pattern of adverse events

relative to the clinical experience in younger patients.

Use in Children and Adolescents aged <18 years

Safety and effectiveness in children have not been established. Duloxetine should not be used in children and

adolescents aged < 18 years.


Genotoxicity

Duloxetine demonstrated no genotoxic potential in a battery of in vitro and in vivo tests, including assays for

gene mutation, chromosomal effects, unscheduled DNA synthesis, and sister chromatid exchange.

Carcinogenicity

Duloxetine was administered in the diet to rats and mice for two years. In rats and male mice there was no

increase in the incidence of tumours. In female mice, there was an increased incidence of hepatocellular

adenomas and carcinomas at the high dose only (144 mg/kg/day which is 5 times the maximum recommended

human dose [MRHD] on a mg/m2 basis). These findings were considered to be secondary to hepatic enzyme

induction with associated centrilobular hypertrophy and vacuolation and their relevance to humans is unknown.

Effects on Laboratory Tests

There are no data available that shows that duloxetine has an effect on laboratory tests.

Effect on Ability to Drive or Operate Machinery

In controlled studies duloxetine has not been shown to impair psychomotor performance, cognitive function or

memory. However, as any psychoactive drug may impair judgement, thinking or motor skills, and duloxetine

may be associated with undesirable effects such as sedation and dizziness, patients should be cautioned about

their ability to perform potentially hazardous tasks until they are reasonably certain that duloxetine therapy does

not affect their ability to engage in such activities.

Labour and Delivery

The effect of duloxetine on labour and delivery in humans is unknown.

INTERACTIONS WITH OTHER MEDICINES

Duloxetine is a SNRI with its primary effect on the CNS. Caution should be used when it is administered in

combination with other centrally acting drugs and substances, especially those with a similar mechanism of

action, including alcohol. Concurrent use with other drugs with serotonergic activity (e.g. SNRIs, SSRIs,

triptans or tramadol) may result in serotonin syndrome (see PRECAUTIONS).

Although duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of

duloxetine with substantial alcohol consumption may be associated with severe liver injury. Isolated cases of

liver failure, including fatal cases, have been reported (see PRECAUTIONS - Hepatotoxicity). Duloxetine

should only be used in exceptional circumstances with extreme caution in patients who consume substantial

amounts of alcohol.

Drugs Metabolised by CYP1A2

Although CYP1A2 is weakly inhibited by duloxetine in vitro, results of a clinical study show that the

pharmacokinetics of a CYP1A2 substrate (theophylline) were not significantly affected by co-administration

with duloxetine (60 mg twice daily). In vitro studies with human hepatocytes demonstrated that duloxetine does

not induce CYP1A2 activity. These studies suggest that duloxetine is unlikely to have a clinically significant

effect on the metabolism of CYP1A2 substrates.

Inhibitors of CYP1A2

As CYP1A2 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of

CYP1A2 will likely result in higher concentrations of duloxetine. Fluvoxamine (100 mg once daily), a potent

inhibitor of CYP1A2, decreased the apparent plasma clearance of duloxetine by about 77%. Duloxetine should

not be used in combination with potent inhibitors of CYP1A2 (e.g., fluvoxamine) (see

CONTRAINDICATIONS).


Drugs Metabolised by CYP2D6

CYP2D6 is moderately inhibited by duloxetine (in common with tricyclic antidepressants and SSRIs).

Duloxetine administered at 60 mg twice daily caused a single 50 mg dose of desipramine (also metabolised

through CYP2D6) to have a 3-fold increase in the AUC. Duloxetine administered at 40 mg twice daily

increased steady-state AUC of tolterodine (2 mg twice daily) by 71% but did not affect the pharmacokinetics of

the 5-hydroxyl metabolite. Therefore, caution should be used if duloxetine is co-administered with medications

that are predominantly metabolised by the CYP2D6 system and which have a narrow therapeutic index (e.g.

tricyclic antidepressants such as nortriptyline and imipramine, phenothiazines, flecainide, propafenone).

Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated

plasma concentrations of thioridazine, duloxetine and thioridazine should not be coadministered.

Inhibitors of CYP2D6

An inhibitor of CYP2D6, paroxetine (20 mg once daily) decreased the oral clearance of duloxetine (40 mg once

daily) by about 37%. Because CYP2D6 is involved in duloxetine metabolism, caution is advised if

administering duloxetine with inhibitors of CYP2D6 (e.g. SSRIs).

Drugs Metabolised by CYP2C9

Although clinical studies have not been performed, results of in vitro studies demonstrate that duloxetine does

not inhibit the enzyme activity of CYP2C9.

Drugs Metabolised by CYP3A

Although clinical studies have not been performed, results of in vitro studies demonstrate that duloxetine does

not inhibit or induce the catalytic activity of CYP3A.

Antacids and H2 Antagonists

Co-administration of duloxetine with aluminium-and magnesium-containing antacids or co-administration of

duloxetine with famotidine had no significant effect on the rate or extent of duloxetine absorption after

administration of a 40 mg oral dose.

Drugs Highly Bound to Plasma Protein

Duloxetine is highly bound to plasma protein (>90%). Administration of duloxetine with another highly protein

bound drug may cause increased free concentrations of either duloxetine or the other drug.

Monoamine Oxidase Inhibitors (MAOI)

Because duloxetine is an inhibitor of both serotonin and noradrenaline reuptake, it is recommended that

duloxetine not be used in combination with an MAOI (see CONTRAINDICATIONS).

St John's Wort

In common with other antidepressants, concomitant administration of duloxetine and the herbal remedy St

John's Wort (Hypericum perforatum) is not recommended.

Warfarin and INR

Increases in INR have been reported when duloxetine was co-administered with warfarin.

Drugs That Affect Gastric Acidity

Duloxetine have an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract

where the pH exceeds 5.5. In extremely acidic conditions, duloxetine, unprotected by the enteric coating, may

undergo hydrolysis to form naphthol. Caution is advised in using duloxetine in patients with conditions that

may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier


release of duloxetine. It is unknown whether the concomitant administration of proton pump inhibitors affects

duloxetine absorption.

ADVERSE EFFECTS

Clinical Trial Data

The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=2327), GAD

(N=668) and DPNP (N=568). The population studied was 17 to 89 years of age; 64.8%, 64.7% and 38.7%,

female; and 85.5%, 77.6%, and 84.6% Caucasian for MDD, GAD and DPNP, respectively. Most patients

received doses of a total of 60 to 120 mg per day.

Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Major Depressive Disorder

Approximately 9% (209/2327) of the patients who received duloxetine in placebo-controlled trials for MDD

discontinued treatment due to an adverse reaction, compared with 4.7% (68/1460) of the patients receiving

placebo. Nausea (duloxetine 1.3%, placebo 0.5%) was the only common adverse reaction reported as a reason

for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the

duloxetine-treated patients and at a rate of at least twice that of placebo).

Generalised Anxiety Disorder

Approximately 15.3% (102/668) of the patients who received duloxetine in placebo-controlled trials for GAD

discontinued treatment due to an adverse reaction, compared with 4.0% (20/495) for placebo. Common adverse

reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included

nausea (duloxetine 3.7%, placebo 0.2%), vomiting (duloxetine 1.3%, placebo 0.0%), and dizziness (duloxetine

1.0%, placebo 0.2%).

Diabetic Peripheral Neuropathic Pain

Approximately 14.3% (81/568) of the patients who received duloxetine in placebo-controlled trials for DPNP

discontinued treatment due to an adverse reaction, compared with 7.2% (16/223) for placebo. Common adverse

reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) were

nausea (duloxetine 3.5%, placebo 0.4%), dizziness (duloxetine 1.6%, placebo 0.4%), somnolence (duloxetine

1.6%, placebo 0.0%), and fatigue (duloxetine 1.1%, placebo 0.0%).

Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in

Placebo-Controlled Trials

Pooled MDD and GAD Trials

Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled

trials that occurred in 2% or more of patients treated with duloxetine and with an incidence greater than

placebo.

Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in MDD and GAD Placebo-

Controlled Trials Percentage of Patients Reporting Reaction

System Organ Class / Adverse Reaction Duloxetine Placebo

(N=2995) (N=1955)

Cardiac Disorders

Palpitations 2A

2

Eye Disorders

Vision blurred 3 2

Gastrointestinal Disorders

Nausea 25 9


Dry mouth 15 6

Diarrhoea 10 7

Constipation* 10 4

Abdominal paina

4 4

Vomiting 5 2

General Disorders and Administration Site

Conditions

Fatigueb

10 6

Investigations

Weight decreased* 2 <1

Metabolism and Nutrition Disorders

Decreased appetitec

7 2

Nervous System Disorders

Dizziness 10 6

Somnolenced

10 4

Tremor 3 <1

Psychiatric Disorders

Insomniae

10 6

Agitationf

5 3

Anxiety 3 2

Libido decreasedg

4 1

Orgasm abnormal1

3 <1

Abnormal dreamsi

2 1

Reproductive System and Breast Disorders

Erectile dysfunctionj

5 1

Ejaculation delayed*j

3 <1

Ejaculation disorderj, k

2 <1

Respiratory, Thoracic, and Mediastinal

Disorders

Yawning 2 <1

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis 6 2

Vascular Disorders

Hot flush 2 <1

A Frequency higher in patients treated with duloxetine but rounded down to whole number

* Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding

three MDD studies which did not have a placebo lead-in period or dose titration.

a Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal

discomfort, and gastrointestinal pain

b Also includes asthenia

c Also includes anorexia

d Also includes hypersomnia and sedation

e Also includes middle insomnia, early morning awakening, and initial insomnia

f Also includes feeling jittery, nervousness, restlessness, tension, and psychomotor agitation

g Also includes loss of libido

h Also includes anorgasmia

i Also includes nightmare

j Males patients only

k Also includes ejaculation failure and ejaculation dysfunction

Diabetic Peripheral Neuropathic Pain

Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients

treated with Duloxetine in the premarketing acute phase of DPNP placebo-controlled trials (doses of 20 to 120

mg/day) and with an incidence greater than placebo.

Table 4: Treatment-Emergent Adverse Reactions Incidence of 2% or More in DPNP Placebo-Controlled

Trials


System Organ Class / Duloxetine

Capsule

Duloxetine

Capsule

Duloxetine

Capsule

Adverse Reaction 20 mg once 60 mg once 60 mg twice Placebo

daily daily daily

(N=115) (N=228) (N=225) (N=223)


Nausea 14 22 30 9

Constipation 5 11 15 3

Diarrhoea 13 11 7 6

Dry mouth 5 7 12 4

Vomiting 6 5 5 4

Dyspepsia 4 4 4 3

Loose stools 2 3 2 1

General Disorders and

Administration Site Conditions

Fatigue 2 10 12 5

Asthenia 2 4 8 1

Pyrexia 2 1 3 1

Infections and Infestations

Nasopharyngitis 9 7 9 5

Metabolism and Nutrition

Disorders

Decreased appetite 3 4 11 <1

Anorexia 3 3 5 <1

Musculoskeletal and Connective

Tissue Disorders

Muscle cramp

Myalgia

5

3

4

1

4

4

3 <1


Somnolence

Headache

Dizziness

Tremor

7

13

6

0

15

13

14

1

21

15

17

5

5

10

6

0


Insomnia 9 8 13 7

Renal and Urinary Disorders

Polyuria 3 1 5 2

Reproductive System and Breast

Disorders

Erectile dysfunction1

0 1 4 0

Respiratory, Thoracic and

Mediastinal Disorders

Cough 6 3 5 4

Pharyngolaryngeal pain 3 1 6 1

Skin and Subcutaneous Tissue

Disorders

Hyperhidrosis 6 6 8 2 1 Male patient only.

The following additional adverse events were reported during placebo-controlled clinical trials of duloxetine for

MDD or other indications in 8504 patients. Very common events are defined as those occurring in >10% of

patients, common events are defined as those occurring in >1% and <10% of patients, uncommon events are

defined as those occurring in >0.1% and <1% of patients, and rare events are defined as those occurring in

<0.1% of patients.


Cardiac Disorders

Common: palpitations.

Uncommon: tachycardia.

Ear and Labyrinth Disorders

Uncommon: vertigo, ear pain, tinnitus.

Endocrine Disorders

Rare: hypothyroidism.

Eye Disorders

Uncommon: mydriasis, visual impairment, dry eye.


Common: dyspepsia (including stomach discomfort), abdominal pain. Uncommon: eructation, gastroenteritis,

stomatitis, halitosis, gastritis, flatulence, gastrointestinal haemorrhage.

General Disorders and Administration Site Conditions

Common: chills (including rigors).

Uncommon: feeling abnormal, feeling hot and/or cold, malaise, thirst.

Rare: gait disturbance

Infections and Infestations

Uncommon: laryngitis.

Investigations

Uncommon: blood pressure increased (including blood pressure systolic increased, blood pressure diastolic

increased), hepatic lab related findings (including alanine aminotransferase increased, hepatic enzyme

increased, aspartate aminotransferase increased, liver function test abnormal, gamma-glutamyltransferase

increased, blood alkaline phosphatise increased, blood bilirubin increased), weight increased, blood cholesterol

increased.

Duloxetine treatment in placebo-controlled clinical trials was associated with small mean increases from

baseline to endpoint in ALT, AST, CPK, and potassium; infrequent, transient, abnormal values were observed

for these analytes in duloxetine-treated patients, compared with placebo-treated patients (see

PRECAUTIONS).

Metabolism and Nutrition Disorders

Uncommon: dehydration.

Musculoskeletal and Connective Tissue Disorders

Common: musculoskeletal pain (including myalgia, neck pain), muscle spasm.

Uncommon: muscle tightness (including musculoskeletal stiffness), muscle twitching.



Very common: headache (placebo rate was more than duloxetine rate in MDD trials).

Common: lethargy, paraesthesia (including hypoaesthesia, hypoaesthesia facia and parasthesia oral).

Uncommon: dysgeusia, disturbance in attention, dyskinesia, poor quality sleep.

Rare: myoclonus.


Common: anxiety, sleep disorder, agitation (including feeling jittery, nervousness, restlessness, tension,

psychomotor agitation).

Uncommon: bruxism, disorientation (including confusional state), apathy, abnormal dreams (including

nightmares).

Renal and Urinary Disorders

Uncommon: nocturia, urinary hesitation, urinary retention, dysuria, polyuria.

Rare: urine odour abnormal, urine flow decreased.

Reproductive System and Breast Disorders

Uncommon: ejaculation disorder (includes ejaculation dysfunction, ejaculation failure), sexual dysfunction,

menopausal symptoms.

Rare: menstrual disorder.

Respiratory, Thoracic and Mediastinal Disorders

Common: yawning, oropharyngeal pain.

Uncommon: throat tightness

Skin and Subcutaneous Tissue Disorders

Common: pruritus

Uncommon: night sweats, photosensitivity reaction, cold sweats, dermatitis contact.

Vascular Disorders

Uncommon: flushing, peripheral coldness, orthostatic hypotension.

Glucose Regulation

In three clinical trials of duloxetine for the treatment of diabetic neuropathic pain, the mean duration of diabetes

was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL (9.78 mmol/L), and the

mean baseline haemoglobin A1c (HbA1c) was 7.81%. In the 12 week acute treatment phase of these studies,

small increases in fasting blood glucose were observed in duloxetine-treated patients. HbA1c was stable in both

duloxetine-treated and placebo-treated patients. In the extension phase of these studies, which lasted up to 52

weeks, there was an increase in HbA1c in both the duloxetine and routine care groups, but the mean increase

was 0.3% greater in the duloxetine-treated group. There was also a small increase in fasting blood glucose and

in total cholesterol in duloxetine-treated patients while those laboratory tests showed a slight decrease in the

routine care group.


Spontaneous Data

The following list of adverse drug reactions is based on post-marketing spontaneous reports involving use of

duloxetine for any indication, and corresponding reporting rates have been provided. Rare events are defined as

those occurring in less than 1/1000 patients; very rare events are those occurring in less than 1/10,000 patients.

Endocrine disorders

Very rare: syndrome of inappropriate antidiuretic hormone (SIADH).

Cardiac disorders

Very rare: supraventricular arrhythmia.

Eye disorders

Very rare: glaucoma.

Gastrointestinal disorders

Very rare: Microscopic colitis.

Hepatobiliary disorders

Very rare: alanine aminotransferase (ALT) increased, alkaline phosphatase increased, aspartate

aminotransferase (AST) increased, bilirubin increased.

Very rare: hepatitis, jaundice.

Isolated cases of liver failure, including fatal cases, have been reported. A majority of these cases have been

reported in patients with past or current risk factors for liver injury, including alcohol abuse, hepatitis or

exposure to drugs with known adverse effects on the liver. (see PRECAUTIONS)

Immune system disorders

Very rare: anaphylactic reaction, hypersensitivity.

Metabolism and nutrition disorders

Very rare: hyponatraemia, hyperglycaemia (reported especially in diabetic patients)

Musculoskeletal and connective tissue disorders

Very rare: trismus

Nervous system disorders

Very rare: Extrapyramidal disorder, serotonin syndrome, seizures, restless legs syndrome, seizures upon

discontinuation.

Psychiatric disorders

Rare: hallucinations.

Very rare: mania, aggression and anger (particularly early in treatment or after treatment discontinuations).

Renal and urinary disorders

Rare: urinary retention.


Reproductive system and breast disorders

Very rare: gynaecological bleeding, galactorrhoea, hyperprolactinaemia

Skin and subcutaneous tissue disorders

Rare: Rash.

Very rare: angioneurotic oedema, contusion, cutaneous vasculitis (sometimes associated with systemic

involvement), Stevens-Johnson Syndrome, urticaria.

Vascular disorders

Very rare: orthostatic hypotension (especially at the initiation of treatment), syncope (especially at initiation of

treatment), hypertensive crisis.

Adverse Events - causality not established

Very rare cases of the following adverse events have been reported in post-marketing experience, but no causal

link between these events and duloxetine has been established.

Abnormal bleeding events e.g. intracerebral, gastrointestinal; blood dyscrasias; cardiac events e.g., myocardial

infarction and ventricular arrhythmias; pancreatitis; renal impairment; rhabdomyolysis; skin reactions

especially in regards to subcutaneous tissue disorder

Discontinuation Symptoms

The most commonly reported symptoms following abrupt or tapered discontinuation of duloxetine in clinical

trials have included dizziness, nausea, headache, paraesthesia, fatigue vomiting, irritability, nightmares,

insomnia, diarrhoea, anxiety, hyperhidrosis, vertigo, and somnolence (see PRECAUTIONS).

DOSAGE AND ADMINISTRATION

Major Depressive Disorder

Duloxetine should be administered for the treatment of major depressive disorder at a dose of 60 mg once daily,

with or without food. There is no adequate evidence suggesting that patients not responding to 60 mg once

daily will benefit from having their dose increased.

Generalised Anxiety Disorder

The recommended starting dose of duloxetine in patients with generalized anxiety disorder is 30 mg once daily

with or without food. The daily dose should be increased in 30 mg increments until the minimum effective dose

is achieved. The maximum dose is 120 mg per day, given as 120 mg once daily. Doses above 120 mg have not

been systematically evaluated.

Initial Tolerability

For patients in whom initial tolerability may be a concern, such as treatment-naive patients or those with a

history of adverse events with other medications, use of a lower starting dose such as 30 mg once daily for one

week before increasing the dose to 60 mg once daily should be considered. A dose of 30 mg once daily should

be used in patients with end stage renal disease (see below). In addition, clinical studies have shown that taking

duloxetine with food may improve initial tolerability.

Discontinuation of treatment

When discontinuing duloxetine after more than one week of therapy it is generally recommended that the dose

be tapered to minimise the risk of discontinuation symptoms. As a general recommendation, the dose of

duloxetine should be reduced by half or administered on alternate days during a period of not less than two


weeks. The precise regimen followed should take into account the individual circumstances of the patient, such

as duration of treatment, dose at discontinuation, etc.

Renal Impairment

A lower dose of 30 mg once daily should be used in patients with end stage renal disease (creatinine clearance

< 30 mL/min) (see PHARMACOLOGY – Pharmacokinetics).

Hepatic Impairment

Duloxetine is contraindicated in patients with liver disease resulting in hepatic impairment (see

PHARMACOLOGY – Pharmacokinetics).

Patients aged > 65 years

No dosage adjustment is recommended for elderly patients on the basis of age (see PHARMACOLOGY –

Pharmacokinetics).

Children and adolescents aged < 18 years

Duloxetine has not been studied in patients under 18 years of age (see PRECAUTIONS)

OVERDOSAGE

On the available evidence there is a wide margin of safety in overdose. In premarketing clinical trials, cases of

acute ingestions up to 1400 mg, alone or in combination with other drugs, have been reported and have not

been fatal. However in post marketing experience, fatal outcomes have been reported for acute overdoses,

primarily with mixed overdoses, but also with duloxetine only, at doses as low as approximately 1000 mg.

Signs and symptoms of overdose (most with mixed drugs) included serotonin syndrome, somnolence, vomiting

and seizures.

In animal studies, the major signs of overdose toxicity are related to the CNS and gastrointestinal systems.

Signs of toxicity include CNS effects such as tremors, clonic convulsions, ataxia, emesis, and decreased

appetite.

Management of Overdose - No specific antidote is known, but if serotonin syndrome ensues, specific treatment

(such as with cyproheptadine and/or temperature control) may be considered. An airway should be established.

Monitoring of cardiac and vital signs is recommended, along with appropriate symptomatic and supportive

measures. Duloxetine has a large volume of distribution and forced diuresis, haemoperfusion, and exchange

perfusion are unlikely to be beneficial.

Contact the Poisons Information Centre on 131126 (Australia) for information on the management of overdose

with duloxetine.

PRESENTATION AND STORAGE CONDITIONS

Coperin Capsules 30 mg : Contains duloxetine hydrochloride equivalent to duloxetine 30mg in Size '3'

Capsule with dark blue cap and white body, imprinted with "DU" in white ink

on cap and "30" in black ink on body, containing six white to off white mini

tablets.

Available in Clear PVC/PE/Aclar/ Peelable Child Resistant Aluminium foil

blisters of 7*, 14* and 28 Capsules.

Coperin Capsules 60 m : Contains duloxetine hydrochloride equivalent to duloxetine 60mg in Size '1'

Capsule with dark blue cap and green body, imprinted with "DU" in white ink

on cap and "60" in black ink on body, containing twelve white to off white


mini tablets.

Available in Clear PVC/PE/Aclar/ Peelable Child Resistant Aluminium foil

blisters of 7*, 14* and 28 Capsules.

* Not marketed in Australia

STORAGE CONDITIONS

Store below 25°C. Store in original package.

NAME AND ADDRESS OF SPONSOR

Alphapharm Pty Limited

Level 1, 30 The Bond

30-34 Hickson Road

Millers Point NSW 2000

ABN 93 002 359 739

www.alphapharm.com.au

POISON SCHEDULE OF THE MEDICINE

S4

DATE OF FIRST INCLUSION IN THE AUSTRALIAN REGISTER OF

THERAPEUTIC GOODS

29 April 2013

DATE OF MOST RECENT AMENDMENT

08/07/2015

coperin_pi\JUL15/00

http://www.alphapharm.com.au/

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